Cell-type-specific requirement for TYK2 in murine immune cells under steady state and challenged conditions

Cell Mol Life Sci. 2025 Mar 2;82(1):98. doi: 10.1007/s00018-025-05625-9.

Anzhelika Karjalainen ¹, Agnieszka Witalisz-Siepracka ¹ ², Michaela Prchal-Murphy ³, David Martin ¹, Felix Sternberg ⁴ ⁵, Milica Krunic ⁶, Marlies Dolezal ⁷, Nikolaus Fortelny ⁸, Matthias Farlik ⁹, Sabine Macho-Maschler ¹, Caroline Lassnig ¹⁰, Katrin Meissl ¹, Lena Amenitsch ¹, Therese Lederer ¹, Elena Pohl ⁴, Dagmar Gotthardt ², Christoph Bock ¹¹ ¹², Thomas Decker ¹³ ¹⁴, Birgit Strobl ¹, Mathias Müller ¹⁵

Affiliations

1 Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
2 Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems an Der Donau, Austria.
3 Pharmacology and Toxicology, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
4 Physiology and Biophysics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
5 Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
6 Campus Tulln, University of Applied Sciences Wiener Neustadt, Wiener Neustadt, Austria.
7 Platform Biostatistics and Bioinformatics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
8 Department of Biosciences and Medical Biology, Center for Tumor Biology and Immunology, Paris-Lodron University Salzburg, Salzburg, Austria.
9 Department of Dermatology, Medical University of Vienna, Vienna, Austria.
10 Core Facility VetBiomodels, University of Veterinary Medicine, Vienna, Austria.
11 Cemm Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
12 Institute of Artificial Intelligence, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria.
13 Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria.
14 Center for Molecular Biology, Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria.
15 Animal Breeding and Genetics, Department of Biological Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria. [email protected].

PMID: 40025196 DOI: 10.1007/s00018-025-05625-9

Abstract

Tyrosine kinase 2 (Tyk2) deficiency and loss or inhibition of kinase activity in men and mice leads to similar immune compromised phenotypes, predominantly through impairment of interferon (IFN) and interleukin 12 family responses. Here we relate the transcriptome changes to phenotypical changes observed in TYK2-deficient (Tyk2^-/-) and Tyk2 kinase-inactive (Tyk2^K923E) mice in naïve splenic immune cells and upon ex vivo IFN treatment or in vivo tumor transplant infiltration. The Tyk2 activities under homeostatic and both challenged conditions are highly cell-type-specific with respect to quantity and quality of transcriptionally dependent genes. The major impact of loss of Tyk2 protein or kinase activity in splenic homeostatic macrophages, NK and CD8⁺ T cells and tumor-derived cytolytic cells is on IFN responses. While reportedly Tyk2 deficiency leads to partial impairment of IFN-I responses, we identified cell-type-specific IFN-I-repressed gene sets completely dependent on Tyk2 kinase activity. Reported kinase-inactive functions of Tyk2 relate to signaling crosstalk, metabolic functions and cell differentiation or maturation. None of these phenotypes relates to respective enriched gene sets in the Tyk2 kinase-inactive cell types. Nonetheless, the scaffolding functions of Tyk2 are capable to change transcriptional activities at single gene levels and chromatin accessibility at promoter-distal regions upon cytokine treatment most prominently in CD8⁺ T cells. The cell-type-specific transcriptomic and epigenetic effects of Tyk2 shed new light on the biology of this JAK family member and are relevant for current and future treatment of autoimmune and inflammatory diseases with Tyk2 inhibitors.

Keywords

CD8+ T cells; Interferon; JAK-STAT; Macrophages; NK cells; Splenic immune cells; Tonic signaling; Tumor-infiltrating cells.

Name
Email *

	Sorry, but the email address you supplied was invalid.